Compound Evaluation and Potency Ranking
It is a well-established fact in basic science, as well as in drug discovery, that the differences between an assay based on a purified or recombinant protein and a full-length protein in a native cellular context may have substantial impact on the data. This will subsequently affect decisions made based on this data. CETSA® can be used to correlate target engagement (TE) in the cell with functional readouts from other assays to strengthen target validation and establish the structure-activity relationship (SAR) of your compound series. Further, CETSA® EC50 data provides you with the relative TE potency of your compound, allowing you to rank and prioritise compounds in a native and physiologically relevant environment such as in a living cell.
Including CETSA® in your assay cascade and using the EC50 data for potency ranking within your chemical series facilitates a relevant compound design yielding compounds with higher chance of therapeutic effect. CETSA® data will help you to focus your efforts on the compounds with the highest potential of success at each stage of drug discovery. In the end, this approach greatly reduces the risk of later-stage, and very costly, failures due to progression of compounds that lack relevant TE. Thus, using CETSA®-based cellular TE data to build your SAR and to drive your compound optimization is highly relevant for medicinal chemists in the compound design and project prioritization.
Tsuyoshi Ishii, Takuro Okai, Misa Iwatani-Yoshihara, et al. CETSA quantitatively verifies in vivo target engagement of novel RIPK1 inhibitors in various biospecimens. (2017) Nature Scientific Reports. DOI: 10.1038/s41598-017-12513-1